Synthesis for the preparation of 3-hydroxy-n-alkylisomorphinans

ABSTRACT

3-HYDROXY-N-ALKYLISOMORPHINANS ARE COMPOUNDS KNOWN TO POSESS VALUABLE PROPERTIES AS NARCOTIC ANALGETICS AND/ OR ANTAGONISTS. THE COMMERCIAL USE OF THESE COMPOUNDS HAS NOT BEEN PRACTICAL DUE TO THE HIGH COST OF MAKING THESE COMPOUNDS. A NEW SYNTHESIS HAS BEEN FOUND WHICH PROVIDES THE COMPOUNDS IN COMMERCIAL YIELDS VIA A TOTAL SYNTHESIS.

United States Patent' Ofice 3,803,150 SYNTHESIS FOR THE PREPARATION OF 3-HYDROXY-N-ALKYLISOMORPHINANS Ivo Monkovic and Henry Wong, Candiac, Quebec, Canada, assignors to Bristol-Myers Company, New York,

Nb brawing. Filed Feb. 24, 1912, Ser. No. 229,201 rm. Cl. 007d 43/28 US. Cl. 260-285 4 Claims BACKGROUND OF THE INVENTION (1) Field of the invention This invention embodies a new process for the preparation of compounds useful as analgetics and/or narcotic antagonists from materials other than opium alkaloids.

(2) Description of the prior art (A) US. Pat. No. 3,285,922 reports morphinans and isomorphinans having the formula in which Y is cyclobutyl or cyclopropyl as possessing analgetic and/or narcotic antagonist activity.

(B) M. Gates and T. Montzka [L Med. Chem., 7, 127 (1964)] report the synthesis of morphinans and isomorphinans of the formula in which Y is cyclopropylethyl, cyclobutylmethyl, 1- phenylcyclopropylmethyl, methyl, cyano, H, etc. and R is methyl or I-I.

(C) M. Gates and W. Webb [1. Am. Chem. Soc., 80, 1186 (1958)] also report similar compounds the most pertinent of which appears to be that having the formula SUMMARY OF THE INVENTION Isomorphinan compounds having the formula 3,803,150 Patented Apr. 9, 1974 wherein R is (lower)alkyl, (lower)al*kenyl, (lower) in which R is H or CH; and n is an integer of 3; or a pharmaceutically acceptable acid addition salt thereof are prepared by the consecutive steps of (A) Acylating the compound having the formula in which R is (lower)alkyl to produce a com-pound having the formula (VII) in which R is as above, R is (lower)alky1, -CF 2)n-' s (lower) alkoxy) in which R is H or CH; and n is an integer of 0 to 2;

(B) Hydrating Compound VII by treatment with boron trihydride and then with hydrogen peroxide in the presence of base to produce the compound having the formula in which R and R are as above;

(C) Esterifying Compound VIII with methylsulfonyl chloride to produce the compound having the formula .3 a ll inc-a" in which R and R are as above;

(D) Cyclizing Compound IX by treatment with sodium hydride to produce a compound having the formula in which R and R are as above.

The remaining consecutive steps of the synthesis will then vary according to the species of Compound XII desired.

When the-ultimate compounds desired are those of the formula D) wherein R is C -C (lower)alkyl,

in which R is H or CH and n is an integer of 1 to 3, one would further perform the steps of (E Reducing Compound X wherein R is (lower) alkyl and R is C -C, (lower)alkyl,

RI e o -41 or --(CH C H in which R is H or (lower)alkyl and n is an integer of 1 or 2 with lithium aluminum hydride to produce the compound having the formula (X111) in which R is (lower)all yl and R is C -C (lower)alxyi,

in which R is H or CH and n is an integer of 1 to 3; and (F Cleaving the ether function of Compound XIp to produce Compound XIIp wherein R is H.

However, when the ultimate species desired are those of the formula I (Xllr) wherein R is CH;,, (lower)alkenyl, (lower)alkynyl, '-(CH C5H5 Ol' *CHr-C=CH1 one would further perform the steps of (E Hydrolyzing Compound X wherein R is (lower) alkyl and R is (lower) alkyl, --CF (lower) alkoxy, phenyl or benzyl to produce the compound having the formula 4 and X is chloro, bromo or iodo, or its functional equivalent as an alkylating agent for a secondary amine, to produce Compound XIr; and

(G Cleaving the ether function of Compound XIr to produce Compound XIIr.

Likewise, when the ultimate species of the compounds desired are those of the formula (xIIs) wherein R is one would further perform the steps of (E Hydrolyzing Compound X wherein R is (lower) R is (lower)alkyl, -CF (lower-)alkoxy, phenyl or benzyl to produce the compound having the formula (F Acylating Compound XIII with an acylating agent having the formula 0 RPJX in which R is a radical of the formula Q Q or C H: and X is chloro, bromo or iodo, or its functional equivalent as an acylating agent for a secondary amine, to produce Compound Xs having the formula (Xs in which R and R are as above;

(G Reducing Compound Xs with lithium aluminum hydride to produce the compound having the formula (x1 wherein R is (lower) alkyl and R is 8 (H Cleaving the ether function of Compound XIs to produce Compound XIIs wherein R is H.

Compounds having the formula in which R is H or methyl and R is cyclopropylmethyl or cyclobutylmethyl are reported in US. Pat. No. 3,285,- 922 to possess valuable analgetic and/or narcotic antagonist activity.

Unfortunately these compounds are not available commercially due to their high cost of synthesis. These compounds, when prepared by the process of the Gates patent, are derived from opium alkaloids; expensive starting materials. In addition, the yields are low and thereby uneconomical.

Drug abuse by thrill-seeking youth or by people looking for an escape from the realities of every day life has become more and more common place in our present society. One class of widely abused drugs are the narcotic analgetics such as codeine, morphine, meperidine, etc. It is because of the high addictive potential of these agents that much time and money are being expended by the pharmaceutical industry and by governments to try and discover and develop new non-addicting analgetics and/ or narcotic antagonists. The compounds of Formula XII appear to possess some of these desirable properties.

It was therefore an object of the present invention to discover a new and economical method of preparing these compounds.

It was a further object to develop a method employing starting materials that were not opium alkaloids or derivatives thereof.

The objectives of the present invention have been achieved by the provision of the process for the total synthesis of compounds having the formula x11 in which R is H or (lower)alkyl and R is selected from the group comprising (lower)alkyl, (lower)alkynyl, -CH2CECH,

and C alkenyl in which R is H or CH, and n is l to 3; from the readily available starting material 7-methoxy- 3,4-dihydro-1 [2H1-naphthalenone.

The compounds of the instant invention have the basic morphinan nucleus numbered and represented by the following plane formula N-a r-a The present invention embodies all of the isomorphinan isomers including the optical isomers in their resolved form.

The optical isomers can be separated and isolated by fractional crystallization of the diastereoisomeric salts formed, for instance, with dor l-tartaric acid or D-(+)- a-bromocamphorsulfonic acid.

For the purpose of this disclosure, the term (lower) alkyl is defined as an alkyl radical containing 1 to 10 carbon atoms in straight or branched chains. The terms (lower)alkynyl and (lower)alkenyl are hydrocarbons of 2-10 carbons with 1 triple bond and 2-10 carbons with 1 double bond respectively. (Lower)alkanol is a straight or branched chain alcohol of 1 to 10 carbon atoms.

For the purpose of this disclosure, the term acid addition salt is defined to include all those inorganic and organic acid salts of the compounds of the instant invention, which salts are commonly used to produce nontoxic salts of medicinal agents containing amine functions. Illustrative examples would be those salts formed by mixing the compounds of Formula I with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric or tartaric acid, and the like.

The compounds of the instant invention are prepared by a total synthesis comprising up to 10 steps. Surprisingly, the synthesis is efiicient and appears commercially feasible. The process is outlined in Charts I, II and HI.

cam: 1

0% ste A a o g cs ago We Example 5 x 0 3 9 VA. VIII:

Example I :A

he a? '5 EXBnEl 15A E 69 0 3 Example 153 a 11 0 ll -C-OC H5 .'I R I 5150 EXAmRlE 1T 5 m A preferred embodiment of the present invention is the process of preparing compounds having the formula 8 wherein R is C -C (lower)alkyl, -(CH -C H in which R is H or 0H; and n is an integer of l to 3; which process comprises the consecutive steps of (A) Acylating one mole of the compound having the formula with at least one mole of an acylating agent having the formula in which X is OH, Cl, Br or I, R is (lower)alkyl, 2)n s 5 e 5 or Cal in which 'R is H or CH and n is an integer of 1 or 2, or a functional equivalent thereof for the acylation of a primary amine, in an inert organic solvent, in the presence of at least one mole of a tertiary amine to produce the compound having the formula in which R and R are as above;

(B) Treating one mole of Compound VIIp with at least two mole of boron trihydride, in an anhydrous organic solvent, and subsequently with at least one mole of hydrogen peroxide and water in the presence of an alkali metal hydroxide to produce the compound having the formula in which R and R are as above;

(C) Esterifying one mole of Compound VIIIp with at least one mole of a (lower) alkyl, benzene or toluene sulfonyl, halide; or its equivalent, in the presence of at least one mole of a tertiary amine in an inert organic solvent, to produce the compound having the formula a iii-a in which R and R are as above;

D) Cyclizing one mole of Compound IXp by treatment with at least one mo e of sodium hydride, in an inert organic solvent, to produce the compound having the formula in which R and R are as above;

(-13.) Reducing one mole of Compound X with an excess of lithium aluminum hydride in an inert solvent with the aid of heat to produce the compound having the formula in which R and R are as above; and

(F) Cleaving the ether function of Compound XIp to produce the compound of Formula XIIp.

Another preferred embodiment is the process for the preparation of Compound XIIp wherein in step (A) one mole of Compound V is acylated with about 1 to about 1.5 moles of acylating agent, in an organic solvent selected from the group comprising methylene chloride, benzene, xylene, ether, dichloroethane or chloroform, in the presence of at least one mole of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine or N-methylpyrrolidine, to produce Compound VIIp; in step (B) one mole of Compound VIIp is treated with about 1.5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group comprising dry tetrahydrofuran, benzene, dioxane, diethyl ether, dipropylethyl or dibutyl ether, for about two to 24 hours, at a temperature in the range of about C. to about 30 C., following which the mixture is treated with at least an equimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound having the Formula VIIIp; in step (C) esterifying one mole of Compound VIIIp with about 1.0 to 2.0 moles of a (lower)alkyl sulfonyl chloride, in the presence of about 1.0 to 3.0 moles of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine or N-methylpyrrolidine, in an organic solvent selected from the group comprising benzene, xylene, toluene, methylene chloride or dichloroethane, to produce Compound IXp; in step (D) cyclizing one mole of Compound IXp by treatment with about 1.0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group comprising dimethylformamide, dimethylacetamide, benzene, toluene, xylene, tetrahydrofuran, dioxane, at about room temperature for a period of about 5 to about 25 hours, to produce Compound Xp; in step (E) reducing one mole of Compound Xp with about 1.0 to about 2.0 moles of lithium aluminum hydride in an organic solvent selected from the group comprising tetrahydrofuran, dioxane, diethyl ether, dipropyl ether or dibutyl ether, with the aid of heat, to produce Compound XIp; and in step F) cleaving the ether function of one mole of Compound XIp by treatment with an agent selected from the group comprising hydrobromic acid, boron tribromide or pyridine hydrochloride to produce Compound XIIp.

A more preferred embodiment is the process for the preparation of Compound XHp wherein in step (A) one mole of Compound V in which R is methyl is acylated 10 with about 1.0 to about 1.2 moles of acylating agent having the formula in which X is Cl, Br or I and R is (lower)alky1, 2)n s 5,

we or a in which R is H or CH, and n is an integer of 1 or 2, in methylene chloride or dichloroethane, in the presence of about 1 to about 2 moles of triethylamine or pyridine to produce Compound VIIp, in step (B) treating one mole of Compound VIIp with about 2 to about 3 moles of boron trihydride in tetrahydrofuran or dioxane, and 1 to 2 moles each of hydrogen peroxide, water and sodium or potassium hydroxide to produce Compound VIIIp; in step (C) esterifying one mole of Compound VIHp with about 1.1 to about 1.6 moles of methylsulfonyl chloride, in the presence of about 1.1 to about 1.6 moles of triethylamine or pyridine in benzene, toluene or xylene to produce Compound IXp; in step (D) cyclizing one mole of Compound IXp with about 1.3 to 1.7 moles of sodium hydride in dirnethylformamide or dimethylacetamide to produce Compound Xp; in step (1E) reducing one mole of Compound Xp with about 1.0 to about 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran or dioxane at about reflux temperatures to produce Compound XIp; and in step (F) cleaving the ether function of XIp by treatment with about 1.5 to about 4.0 moles of boron tribromide, hydrobromic acid or pyridine hydrochloride to produce Compound XIIp.

A most preferred embodiment is the process for the preparation of Compound XIIp in which R is CHPQ or CH wherein the step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to about 1.2 moles of cyclobutylcarbonyl chloride or cyclopropyl carbonyl chloride in methylene chloride, in the presence of 1.0 to 1.3 moles of triethylamine to produce Compound VIIp; in step (B) treating one mole of Compound VIIp with about 2 to 3 moles of boron trihydride in tetrahydrofuran, followed by 1.0 to 1.3 moles each of hydrogen peroxide, water and sodium hydroxide with the aid of heat to produce Compound VIIIp; in step (C) esterifying one mole of Compound VIlIp with about 1.1 to 1.3 moles of methylsulfonyl chloride, in the presence of 1.1 to 1.3 moles of triethylamine in anhydrous benzene to produce Compound IXp; in step (D) cyclizing one mole of Compound D(p with about 1.4 to 1.6 moles of sodium hydride in dimethylformamide to produce Compound Xp; in step (E) reducing one mole of Compound Xp with about 1.0 to 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran to produce Compound XIp; and in step (F) cleaving the ether function of XIp by treatment with about 1.5 to 2.5 moles of boron tribromide to produce Compound XIIp.

A preferred embodiment of the present invention is the process for the preparation of compounds having the formula which process comprises the consecutive steps of (A) Acylating one mole of the compound having the formula in which R is (lower) alkyl, with at least one mole of an acylating agent having the formula in which X is OH, Cl, Br or I, R is (lower)alkyl, CF (lower)alkoxy, phenyl, phenoxy, benzyl or benzyloxy, or its functional equivalent for the acylation of a primary amine in the presence of at least one mole of a tertiary amine to produce the compound having the formula (B) Treating one mole of Compound VIIr with at least one mole of boron trihydride, in an organic solvent, and subsequently with at least one mole of hydrogen peroxide and water in the presence of an alkali metal hydroxide to produce the compound having the formula (V IIIr) in which R and R are as above;

(C) Esterifying one mole of Compound VIIIr with at least one mole of a (lower) alkyl, benzene or toluene sulfonyl halide, or its equivalent, in the presence of at least one mole of a tertiary amine to produce the compound having the formula in which R and R are as above;

(D) Cyclizing one mole of Compound IXr by treatment with at least one mole of sodium hydride, in an inert solvent to produce the compound having the formula in which R and R are as above;

12 (E) Hydrolyzing Compound Xr with an alkali metal hydroxide to produce the compound having the formula in which R is as above; (F) Alkylating Compound XIII with at least an equimolar quantity of an alkylating agent having the formula in which R is (lower)alkyl, (lower)alkenyl, (lower) alkynyl, benzyl or -CHz-O=CH2 and X is chloro, bromo or iodo, or its functional equivalent for alkylating a secondary amine, to produce the compound hawng the formula in which R and R are as above; and

(G) Cleaving the ether function of Compound XII to produce Compound XIIr.

Another preferred embodiment is the process for the preparation of Compound XIIr wherein in step (A) one mole of Compound V is acylated with about 1 to about 1.5 moles of acylating agent, in an organic solvent selected from the group comprising methylene chloride, benzene, xylene, ether, dichloroethane, or chloroform, in the presence of at least one mole of a tertiary amine selected from the group comprising triethylarnine, trimethylamine, pyridine, N-methylpiperidine or N-methylpyrroli'cline to produce Compound VIIr; in step (B) one mole of Compound VIIr is treated with about 1.5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group comprising dry tetrahydrofuran, benzene, dioxane, diethyl ether, dipropyl ethyl or dibutyl ether, for about 2 to 24 hours, at a temperature in the range of about 0 C., to about 30 C., following which the mixture is treated with at least an equimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound having the Formula VHIr; in step (C) esterifying one mole of Compound VIIIr with about 1.0 to 2.0 moles of a (lower) alkylsulfonyl chloride, in the presence of about 1.0 to 3.0 moles of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, in an organic solvent selected from the group comprising benzene, xylene, toluene, methylene chloride or dichloroethane, to produce Compound 'IXr; in step (D) cyclizing one mole of Compound IXr by treatment with about 1.0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group comprising dimethylformamide, dimethylacetamide, benzene, toluene, xylene, tetrahydrofuran, dioxane, at about room temperature for a period of about 5 to about 24 hours, to produce Compound Xr; in step (E) hydrolyzing Compound Xr with at least an equimolar quantity of sodium or potassium hydroxide in a mixture of water and a (lower) alkanol with the aid of heat to produce Compound XIII; in step (F) alkylating one mole of Compound XIII with about 1 to about 2 moles of alkylating agent in the presence of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, n-methylpiperidine, N-methylpyrrolidine, in a (lower)alkanol to produce the Compound XIr; and in step (G) cleaving the ether function of one mole of Compound Xlp by treatment with an agent selected from the group comprising =boron tribromide or pyridine hydrochloride to produce Compound XHp.

A more preferred embodiment is the process for the preparation of Compound XIIr wherein in step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to about 1.2 moles of acylating agent in methylene chloride or dichloroethane, in the presence of about 1 to about 2 moles of triethylamine or pyridine to produce Compound VIIr, in step (B) treating one mole of Compound VIIr with about 2 to about 3 moles of boron trihydride in tetrahydrofuran or dioxane, and l to 2 moles of hydrogen peroxide, water and sodium or potassium hydroxide with the aid of heat to produce Compound VIIIr; in step (C) esterifying one mole of Compound VIIIr with about 1.1 to about 1.6 moles of methylsulfonyl chloride, in the presence of about 1.1 to about 1.6 moles of triethylamine or pyridine in benzene, toluene or xylene to produce Compound IXr; in step D cyclizing one mole of Compound IXr with about 1.3 to 1.7 moles of sodium hydride in dirnethylformamide or dimethylacetamide to produce Compound Xr; in step (E) hydrolyzing one mole of Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower)alkanol with the aid of heat to produce Compound XIIIa; in step (F) alkylating one mole of Compound )GIIa with about 1.2 to 1.7 moles of alkylating agent in the presence of triethylamine or pyridine with the aid of heat in a (lower)alkanol to produce the Compound XIr; and in step (G) cleaving the ether function of XIr by treatment with about 1.5 to about 4.0 moles of boron tribromide or pyridine hydrochloride to produce Compound XIIr.

A most preferred embodiment is the process for the preparation of compound XIIr in which R is wherein in step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to 1.3 moles of ethyl chloroformate or trifiuoroacetic acid anhydride in methylene chloride, in the presence of 1.0 to 1.3 moles of triethylamine to produce Compound VIIr; in step (B) treating one mole of Compound VIIr with about 2 to 3 moles of boron trihydride in tetrahydrofuran, followed by 1.0 to 1.3 moles each of hydrogen peroxide, water and sodium hydroxide with the aid of heat to produce Compound VIIIr; in step (C) esterifying one mole of Compound VIIIr with about 1.1 to 1.3 moles of methylsulfonyl chloride, in the presence of 1.1 to 1.3 moles of triethylamine in anhydrous benzene to produce Compound IXr; in step (D) cyclizing one mole of Compound IXr with about 1.4 to 1.6 moles of sodium hydride in dimethylformamide to produce Compound Xr; in step (E) hydrolyzing Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower) alkanol at about reflux temperature to produce Compound XHIa; in step (F) alkylating one mole of Compound XIIIa with about 1.2 to 1.5 moles of allyl bromide, 1,1-dimethylallyl bromide or 2-chloroal1yl bromide in the presence of triethylamine at about reflux temperatures for about 4 to hours in ethanol, npropanol, isopropanol or n-butanol to produce Compound XIr; and in step (G) cleaving the ether function of XIr.

by treatment with about 1.5 to 4.0 moles of boron bromide or pyridine hydrochloride to produce Compound XIIr.

14 A preferred embodiment of the present invention is the process for the preparation of compounds having the formula wherein R is -om-, -oH;-

which process comprises the consecutive steps of (A) Acylating one mole of the compound having the formula or -CH24 I in which R is (lower)alkyl, with at least one mole of an acylating agent having the formula in which X is OH, Cl, Br or I, R is (lower)alkyl, CF (lower)alkoxy, phenyl, phenoxy, benzyl or benzyloxy, or its functional equivalent for the acylation of a primary amine in the presence of at least one mole of a tertiary amine to produce the compound having the formula tie (VIIIr) in which R and R are as above;

(C) Esterifying one [mole of Compound VIIIr with at least one mole of a (lower)alkyl, benzene or toluene sulfonyl halide, or its equivalent, in tthe presence of at least one mole of a tertiary amine to produce the compound having the formula 080 (lower) alkyl 0 in which R and R are as above;

(D) Cyclizing one mole of Compound IXr by treatment with at least one mole of sodium hydride, in an inert solvent, to produce the compound having the formula in which R and R are as above;

(E) Hydrolyzing Compound Xr with an alkali metal hydroxide to produce the compound having the formula (XIII) in which R is as above;

(F) Acylating Compound XIII with at least an equimolar quantity of an acylating agent having the formula in which R is and X is chloro, bromo or iodo, or its functional equivalent for alkylating a secondary amine, to produce the compound having the formula in which R and R are as above;

(G) Reducing one mole of Compound Xs with an excess of lithium aluminum hydride in an inert solvent with the aid of heat to produce the compound having the formula i (ms) in which R is (lower)alkyl and R1 is or CH,%

and

duce Compound VIIr; in step (B) one mole of Compound VIIr is treated with about 1.5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group comprising dry tetrahydorfuran, benzene, dioxane, diethyl ether, dipropyl ethyl or dibutyl ether, for about 2 to 24 hours, at a temperature in the range of about 0 C., to about 30 0., following which the mixture is treated with at least an equimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound having the Formula VIIIr; in step (-C) esterifying one mole of Compound VHIr with about 1.0 to 2.0 moles of a (lower) alkylsulfonyl chloride, in the presence of about 1.0 to 3.0 moles of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, in an organic solvent selected from the group comprising benzene, xylene, toluene, methylene chloride or dichloroethane, to produce Compound IXr; in step (D) cyclizing one mole of Compound lXr by treatment with about 1.0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group comprising dimethylformamide, dimethylacetamide, benzene, toluene, xylene, tetrahydrofuran, dioxane, at about room temperature for a period of about 5 to about 24 hours, to produce Compound Xr; in step (E) hydrolyzing Compound Xr with at least an equimolar quantity of sodium or potassium hydroxide in a mixture of water and a (lower)alkanol with the aid of heat to produce Compound XIII; in step (F) acylating one mole of Compound XIII with about 1 to about 1.5 moles of acylating agent in the presence of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, n-methylpiperidine, N-methylpyrrolidine, in an organic solvent selected from the group comprising methylene chloride, benzene, xylene, ether, dichloroethane or chloroform, in the presence of at least one mole of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine or N-methylpyrrolidine, to produce Compound Xs; in step (G) reducing one mole of Compound Xs with about 1.0 to about 2.0 moles of lithium aluminum hydride in an organic solvent selected from the group comprising tetrahydrofuran, dioxane, diethyl ether, dipropyl ether or dibutyl ether, with the aid of heat, to produce Compound XIs; and in step (H) cleaving the ether function of one mole of compound XIs by treatment with an agent selected from the group comprising boron tribromide or pyridine hydrochloride to produce Compound XIIs.

A more preferred embodiment is the process for the preparation of Compound XIIr wherein in step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to about 1.2 moles of acylating agent in methylene chloride or dichloroethane, in the presence of about 1 to about 2 moles of triethylamine or pyridine to produce Compound VIIr, in step (B) treating one mole of Compound VIIr with about 2 to about 3 moles of boron trihydride in tetrahydrofuran or dioxane, and 1 to 2 moles of hydrogen peroxide, water and sodium or potassium hydroxide with the aid of heat to produce Compound VIIIr; in step (C) esterifying one mole of Compound VIIIr with about 1.1 to about 1.6 moles of methylsulfonyl chloride, in the presence of about 1.1 to about 1.6 moles of triethylamine or pyridine in benzene, toluene or xylene to produce Compound IXr; in step (D) cyclizing one mole of Compound IXr with about 1.3 to 1.7 moles of sodium hydride in dimethylformamide or dimethylacetamide to produce Compound Xr; in step (E) hydrolyzing one mole of Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower) alkanol with the aid of heat to produce Compound XIIIa; in step (F) acylatin one mole of Compound XIIIa with about 1.2 to 1.7 moles of acylating agent in the presence of triethylamine or pyridine with the aid of heat in methylene chloride or dichloroethane, to produce the Com p und Xs', in step ((3) reducing one mole of Compound 17 Xs with about 1.0 to about 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran or dioxane at about reflux temperatures to produce Compound XIs; and in step (F) cleaving the ether function of XIs by treatment with about 1.5 to about 4.0 moles of boron tribromide or pyridine hydrochloride to produce Compound XHs.

A most preferred embodiment is the process for the preparation of Compound XIIs wherein the step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to 1.3 moles of ethyl chloroformate or trifluoroacetic acid anhydride in methylene chloride, in the presence of 1.0 to 1.3 moles of triethylamine to produce Compound VIIr; in step (B) treating one mole of Compound VIIr with about 2 to 3 moles of boron trihydride in tetrahydrofuran, followed by 1.0 to 1.3 moles each of hydrogen peroxide, water and sodium hydroxide with the aid of heat to produce Compound VIIIr; in step (C) esterifying one mole of Compound VIIIr with about 1.1 to 1.3 moles of methylsulfonyl chloride, in the presence of 1.1 to 1.3 moles of triethylamine in anhydrous benzene to produce Compound IXr; in step (D) cyclizing one mole of Compound IXr with about 1.4 to 1.6 moles of sodium hydride in dimethylformamide to produce Compound Xr; in step (F) hydrolyzing Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower)alkanol at about reflux temperature to produce Compound XlIIa; in step (F) acylating one mole of Compound XIHa with about 1.0 to 1.2 moles of acylating agent in the presence of 1.0 to 1.3 moles of triethylamine at about reflux temperatures in methylene chloride to produce Compound Xs; in step (G) reducing one mole of Compound Xs with about 1.0 to 1.5 moles of lithium aluminum hydride in anhydrous tetrahydrofuran to produce Compound XIs; and in step (H) cleaving the ether function of ms by treatment with about 1.5 to 2.5 moles of boron tribromide to produce Compound XIIs.

A preferred embodiment of the present invention is the prolcess for the preparation of compounds having the formu a (XIIIb) in which R is H or (lower) alkyl, which process comprises the consecutive steps of (A) acylating one mole of the compound having the formula with at least one mole of an acylating agent having the formula of a tertiary amine to produce the compound having the formula v in which R and R are as above;

(B) Treating one mole of Compound VHr with at least one mole of boron trihydride, in an organic solvent, and subsequently with at least one mole each of hydrogen peroxide and water in thepresence of. an alkali metal hydroxide to produce the compound having the formula R o H N-C-R (VIIIr) (IXr) in which R and R are as above;

(D) Cyclizing one mole of Compound lXr by treatment with at least one mole of sodium hydride, in an inert solvent, to produce the compound having the formula in which R and R are as above;

(E) Hydrolyzing Compound Xr with an alkali metal hydroxide to produce the compound having the formula (XIII) in which R is as above; and if desirable,

(F) Cleaving the ether function of Compound XIII to produe Compound XIIIc.

Another preferred embodiment is the process for the preparation of Compound XIH wherein in step (A) one mole of Compound V is acylated with about 1 to about 1.5 moles of acylating agent, in an organic solvent selected from the group comprising methylene chloride, benzene, xylene, ether, dichloroethane or chloroform, in the presence at least one mole of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N methylpiperidine or N-methylpyrrolidine to produce Compound VIIr; in step (B) one mole of Compound VIIr is treated with about 1.5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group comprising dry tetrahydrofuran, benzene, dioxane, diethyl ether, dipropyl ether or dibutyl ether for about two to 24 hours, at a temperature in the range of about 0 C. to about 30 C., following which the mixt-ure is treated with at least an eqnimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound having the Formula VIIIr; in step (C) esterifying one mole of Compound VIIIr with about 1.0 to 2.0 moles of a (lower) alkylsnlfonyl chloride, in the presence of about 1.0 to 3.0 moles of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, in an organic solvent selected from the group comprising benzene, xylene, toluene, methylene chloride or dichloroethane, to produce Compound IXr; in step (D) cyclizing one mole of Compound IXr by treatment with about 1.0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group comprising dimethylformamide, dimethylacetarnide, benzene, toluene, xylene, tetrahydrofuran, dioxane, at about room temperature for a period of about to about 24 hours, to produce Compound Xr; in step (E) hydrolyzing Compound Xr with at least an equimolar quantity of sodium or potassium hydroxide in a mixture of water and a (lower)alkan0l with the aid of heat to produce Compound XIII; and if desirable, in step (F) cleaving the ether function of Compound XIII by treatment with an agent selected from the group comprising hydrobromic acid, pyridine hydrochloride and boron tribromide to produce Compound XIIIc.

A more preferred embodiment is the process for the preparation of Compound XIIIb wherein in step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to about 1.2 moles of acylating agent in methylene chloride or dichloroethane, in the presence of about 1 to about 2 moles of triethylamine or pyridine to produce Compound VIIr; in step (B) treating one mole of Compound VIIr with about 2 to about 3 moles of boron trihydride in tetrahydrofuran or dioxane, and 1 to 2 moles each of hydrogen peroxide, water and sodium or potassium hydroxide with the aid of heat to produce Compound VIIIr; in step (C) esterifying one mole of Compound VIIIr with about 1.1 to about 1.6 moles of methylsulfonyl chloride, in the presence of about 1.1 to about 1.6 moles of triethylamine or pyridine in benzene, toluene or xylene to produce Compound IXr; in step (D) cyclizing one mole of Compound IXr with about 1.3 to 1.7 moles of sodium hydride in dimethylformamide or dimethylacetamide to produce Compound Xr; in step (E) hydrolyzing one mole of Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower)alkanol with the aid of heat to produce Compound XIIIa; and when so desired, in step (F) cleaving the ether function of one mole of Compound XIIIa by treatment with about 1.5 to about 4.0 moles of boron tribromide, hydrobromic acid or pyridine hydrochloride to produce Compound XIIIr.

A most preferred embodiment. is the process for the preparation of Compound XIIIb wherein in step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to 1.3 moles of ethyl chloroformate or trifluoroacetate acid anhydride in methylene chloride, in the presence of 1.0 to 1.3 moles of triethylamine to produce Compound VIIr; in step (B) treating one mole of Compound VIIr with about 2 to 3 moles of boron trihydride in tetrahydrofuran, followed by 1.0 to 1.3 moles each of hydrogen peroxide, water and sodium hydroxide with the aid of heat to produce Compound VIIIr; in step (C) esterifying one mole of Compound VIIIr with about 1.1 to 1.3 moles of methylsulfonyl chloride, in the presence of 1.1 to 1.3 moles of triethylamine in anhydrous benzene to produce Compound IXr; in step (D) cyclizing one mole of Compound IXr with about 1.4 to 1.6 moles of sodium hydride in dimethylformamide to produce Compound Xr; in step (E) bydrolyzing Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower) alkanol at about reflux temperatures to produce Compound XIIIa; and when desired, in step (F) cleaving the ether function of one mole of Compound XIIIa by treatment with about 1.5 to 4.0 moles of boron tribromide, hydrobromic acid or pyridine hydrochloride to produce Compound XIIIc.

20 A preferred embodiment of the present invention is the compound having the formula in which R is H or (lower)all yl,

A more preferred embodiment is the compound havlng the formula in which R is (lower)alkyl.

A most preferred embodiment is the compound having the formula in which R is H or methyl.

'A preferred embodiment of the present invention is the process for the preparation of the compounds having the formula in which R is H or CH and n is an integer of I to 3; which process comprises 'the consecutive steps of (A) Treating one. mole of the compound having the formula i (XIII) in which R is (lower)alkyl with at least one mole of an acylat'ing or alkylating agent having the formula in which W is a radical of the formula C -C (lower) alkynyl, C -C tIlower) alkyl, C -C -(lower)alkynyl,

21 in which R is H or CH and n is an integer of 1 to 2, Z is carbonyl (XXXa in which R and W are as above; and

(C) Cleaving the ether function of Compound XXXa to produce Compound XII.

Another preferred embodiment is the process for the preparation of Compound )GI wherein in step (A) one mole of Compound XIII is alkylated or acylated with about 1.0 to about 2.0 moles of alkylating or acylating agent in an inert organic solvent in the presence of a tertiary amine selected from the group comprising triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, with or without the aid of heat to produce Compound XXX or XXXa; in step (B) treating one mole of Compound XXX with about 1 to about 2 moles of lithium aluminum hydride, in a solvent selected from the group comprising dioxane, tetrahydrofuran, diethyl ether, dipropyl ether and dibutyl ether, with the aid of heat, to produce Compound XXXa; and in step (C) cleaving the ether function of one mole of Compound XXXa with about 1 to about 4 moles of an agent selected from the group comprising hydrobromic acid, boron tribromide or pyridine hydrochloride to produce Compound XII.

For the purpose of this disclosure the term inert organic solvent means an organic solvent that does not participate in the reaction to the extent that it emerges unchanged from the reaction. Such solvents are methylene, chloride, chloroform, dichloroethane, tetrachloromethane, benzene, toluene ether, ethyl acetate, xylene, tetrahydrofuran, dioxane, dimethylacetamide, dimethylformamide, and the like when an acid halide is employed. When an alkylation reaction is being performed, the inert solvent used may also include (lower) alkanols such as methanol, ethanol, n-propanol, isopropanol and the like. The term organic tertiary amine means a tertiary amine commonly employed as a proton acceptor in alkylation and acylation reactions. Such amines are tri(lower)alkylamines, e.g., trimethylamine, triethylamine, and the like, pyridine, dimethylaniline, N-methylpiperidine, and the like.

PREPARATION OF THE STARTING MATERIALS (XIIIa) 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro- 6-methoxyphenanthrene Step A: i w

3,4-dihydro-7-methoxy-2,Z-tetramethylene-1- (2H)naphthalenone (IIa) A nitrogen atmosphere was maintained throughout the following reaction. To a stirred and refluxing suspension of 12 g. (0.5 mole) of sodium hydride in ml. of dry benzene was added during 30 minutes, 16.6 g. (0.2 mole) of anhydrous t-amyl alcohol. The reaction mixture was stirred and refluxed during 15 minutes, and then a solution of 35.2 g. (0.2 mole) of 7-methoxy-3,4-dihydro-1 (2H)-naphthalenone (Ia) in 100 ml. of dry benzene was added dropwise. After another 15 minutes, 54.0 g. (0.25 mole) of 1,4-dibromobutane were added over a period of 15 minutes followed by 100 ml. of dry benzene. The resulting reaction mixture was stirred and refluxed during 50 hours. It was then cooled, washed twice with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residual yellow oil was dissolved in 400 ml. of petroleum ether (B.P. 30-60 C.), treated with charcoal, filtered and the solvent evaporated. The resulting clear light yellow oil (45.7 g.) was distilled at reduced pressure and the fraction boiling at -123 C./0.05 mm. was collected. This procedure yielded 29.4 g. (65%) of colorless spiro ketone 11a. The infrared (IR) and nuclear magnetic resonance (NMR) spectra were consistent with the structure.

Analysis.Calcd for C H O (percent): C, 78.22; H, 7.88. Found (percent): C, 77.96; H, 7.93.

Step B:

1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene- 1-naphthaleneacetonitrile IIIa To a stirred solution of 13.8 ml. (0.022 mole) of 1.6 M n-butyl lithium in hexane at 80 C. under nitrogen was rapidly added 13.8 ml. of anhydrous tetrahydrofuran (TI-IF) followed immediately by a solution of 0.82 g. (0.02 mole) of acetonitrile in 20 ml. THF which was added during 7 minutes. After stirring for 1 hour at 80 C., the resulting white suspension was treated dur ing 5 minutes with a solution of 4.60 g. (0.02 mole) of the spiroketone 11a in 20 ml. THF. The cold bath was removed and the solution was stirred for 10 minutes before it was poured into ice-water acidified with hydro- Cll'lOl'lO acid. The layers were separated, and the aqueous layer was extracted with three 25 ml. portions of benzene.

After drying over anhydrous sodium sulfate, evaporation of the solvent and recrystallization of the remaining solid from chloroform, there was obtained 4.4 g. (80%) of white solid IIIa, -M.P. -442" C. The IR and NMR spectra were consistent with the structure.

Analysis.Calcd for c qHz No'g (percent): C, 75.24; H, 7.80; N, 5.16. Found (percent): C, 75.12; H, 7.91;

ca 0 3 no To a stirred suspension of 0.57 g. (0.015 mole) of lithium aluminum hydride in 20 ml. anhydrous tetrahydrofuran (TI-IF) under N was added a solution of 2.71 g. (0.01 mole) of IIIa in 20 ml. tetrahydrofuran. The reaction mixture was stirred for 4 hours at room temperature (r.t.). It was then cooled and treated with 0.6 ml. of water. The inorganic material was filtered oil and washed well with ether. The filtrate was extracted with two portions of 15 ml. of 1 N hydrochloric acid. The extract was basified with aqueous ammonia, and the free base was taken up in ether. After drying over anhydrous sodium sulfate and evaporation of the solvent, there was obtained 2.2 g. of slightly yellow oil IVa. It was converted to the oxalate salt in acetone and recrystallized from methanol. This procedure yielded 2.9 g. (76%) of white solid, containing 1 mole of methanol of crystallization; M.P. 178-180 C.

In another experiment lVa was obtained from Ila without isolation of 11121 as follows:

4.6 g. (0.02 mole) of the spiroketone 11a in 20 ml. of tetrahydrofuran was converted to the nitrile IIIa according to the procedure described in column 22. To the resulting cold solution (80 C.) of IIIa, was added 1.14 g. (0.03 mole) of lithium aluminum hydride in small portions. After the addition had been completed, the reaction mixture was stirred at r.t. for 4 hours. After work up as above, there was obtained 5.7 g. (75% overall) of the oxalate salt of Na, M.P. 179-170 C. In both procedures, the IR and NMR spectra were consistent with the desired product.

Analysis.-Calcd for C H NO .C H .CH OH (percent): C, 63.31; H, 7.70; N, 3.69. Found (percent): C, 63.41; H, 7.43; N, 3.79.

Step D:

4a-(2-aminoethyl) -1,2,3 ,4,4a,9-hedahydro-6- methoxyphenanthrene (Va) Method A. Compound IVa [1.50 g. (000548)] (free base liberated from 2 g. of oxalate salt) in ml. of ether was treated with 1.5 ml. of concentrated HCl under N at 55-60 C. for 5 hours. To the cooled mixture were added in succession 10 ml. of ether and 10 ml. of water. After shaking, the two layers were separated. The acidic layer was made alkaline with aqueous ammonia and extracted with ether. The ether layer was dried (K CO and concentrated to yield 1.30 g. of pale yellow oil Va. It was converted to an oxalate salt in acetone. The crys tals were filtered and washed with a small amount of methylene chloride. The IR and NMR spectra were con sistent with the structure.

Yield 1.7 g. (96%) of white solid, M.P. 187-213 C.

Analysis.Calcd for C H 'NO-C H O (percent): C, 65.69; H, 7.25; N, 4.03. Found (percent): C, 65.46; H, 7.20; N, 3.85.

Method B: 120 g. of the oxalate salt of Na was slurried in 700 ml. of water, and to it was added 400 ml. of henzene and 60 ml. of concentrated ammonia. The mixture was stirred until all the solid had disappeared (ca. 15 minutes) and then the layers were separated. The water layer was extracted with another 100 ml. of benzene, and the combined benzene layers were shaken with 200 ml. of saturated NaCl solution, filtered over K CO and concentrated in vacuo. The residual oil (ca. 90 g.) was dissolved in 300 ml. of ether in a one 1. round bottom flask and while cooling with an ice-water bath and swirling, to it was added carefully 90 ml. of concentrated HCl and then gently refluxed on the steambath for three hours in a closed system using an oil bubbler. Then the layers were separated, and to the water layer was added 150 ml. of water. After cooling, the solid was filtered off and washed with ml. of acetonitrile to yield 80-85 g. of the HCl salt. From the mother liquor a further crop of the produee can be obtained by liberating the free base and repeating HCl treatment as above. The product was recrystallized as the hydrochloride from methanol-ether; MP. 135 C. (dec.).

Analysis.-Calcd for C1'1H23NO'HC1CH3OH (percent): C, 66.34; H, 8.66; N, 4.29. Found (percent): C, 66.34; H, 8.02; N, 4.46.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 it na n c- C830 cu o (Va) (VIIa.)

To a cooled (ice bath) and stirred solution of 25.0 g. of Va and 11.0 g. of triethylamine in ml. of CH CI was added dropwise a solution of 10.5 g. (0.1 mole) of cyclopropyl carbonyl chloride in 15 ml. CH CI during 15 minutes. The reaction mixture was treated with water and the layers separated. The organic layer was dried (Na SO and evaporated to dryness. The residual oil was treated with 30 ml. of ether and after standing for 2 hours at r.t. it crystallized. It was filtered to give 25.56 g. of white solid M.P. -125 C. Recrystallization from methanol afforded analytical sample, M.P. 126-130 C., of Compound VIIa. The infrared (IR) and nuclear magnetic resonance (NMR) spectra were consistent with the structure.

Analysis.--Calcd for C21H2'7NO2 (percent): C, 77.50; H, 8.36; N, 4.30. Found (percent): C, 77.21; H, 8.40; N, 4.09.

Example 2 OH O (VIIa) 52 ml. of approximately 1 M boron trihydride/tetrahydrofuran (THF) solution was added to a solution of 6.50 g. (20 mmole) of VIIa. in 25 ml. dry THF, and the resulting reaction mixture was let standing at r.t. for 4 hours. It was then decomposed with 1 ml. H 0, 9 ml. 5 N NaOH, and 2.9 ml. 30% H 0 The reaction mixture was refluxed for 20 minutes, cooled, treated with water and acidified with concentrated HCl. The acidic solution was extracted with benzene, and the benzene solution was dried (Na SO and evaporated to dryness to yield 4.22 g. of a neutral oil. The acidic solution was basified with NH OH, and extracted with CH Cl The CH CI solution was dried and evaporated to dryness to yield 1.9 g. of basic oil.

The neutral oil containeda mixture of product Villa and an unknown side product. 2.2 g. of product VIIIa was obtained as a white crystalline solid (M.P. 117") by treating the crude oil with ether and allowing it to stand at r.t. to crystallize. The analytical sample of VIIIa was recrystallized twice from CH Cl -ether, M.P. 130-131 C. The IR and NMR spectra were consistent with the structure. 1

Analysis.Calcd for C H NO (percent): C, 73.44; H, 8.51; N, 4.08. Found (percent): C, 73.40; H, 8.59; N, 4.07.

(VIIIa) VIIIa.

To a solution of 1.94 g. (5.648 mmole) of Villa and 0.808 g. (8 mmole) of triethylamine in 30 ml. dry benzene was added dropwise with cooling (ice bath) a solution of 8 ml. (8 mmole) of a 1 M mesyl chloride in benzene. The reaction mixture was left at r.t. for 3 hours. It was treated with water and the layers separated. The benzene solution was washed with dilute HCl and water. It was dried (Na SO and evaporated to dryness to yield a solid residue. This was treated with ether and filtered to give 2.2 g. of IXa (M.P. 120-122 C.). Analytical sample recrystallized from CH Cl ether, M.P. 123-124 C. The IR and NMR were consistent with the structure.

Analysis.Calcd. for C H NO S (percent); C, 62.88; H, 7.41; N, 3.32. Found (percent): C, 62.32; H, 7.39; N, 3.18.

Example 4 To a cooled (ice salt bath) and stirred suspension of 0.126 g. (5.25 mmole) of NaH in 5 ml. dry DMF was added dropwise a solution 1.48 g. (3.35 mmole) of IXa in ml. dry DMF. The reaction mixture was stirred at r.t. for 18 hours. It was decomposed with water and extracted with benzene. The benzene extracts were dried and evaporated to dryness to give 1.2 g. of Xa. Analytical sample was distilled B.P. 165170/0.0l-0.05. The IR and NMR were consistent with the structure.

Analysis.-Calcd. for C H NO (percent): C, 77.50; H, 8.37; N, 4.30. Found (percent): C, 77.56; H, 8.44; N, 4.15.

Example 5 A solution of 46.2 g. (0.22 mole) of trifluoroacetic anhydride in 50 ml. of CH Cl was added dropwise to a cooled (ice-bath) and stirred solution in 51.4 g. (0.2 mole) of Va and 22.22 g. (0.22 mole) of triethylamine in 150 ml. of CH Cl The reaction mixture was decomposed with ice-water and the layers separated. The CH Cl solution was washed with dilute HCl, water and then dried (Na SO It was evaporated to dryness to yield a solid residue weight 67.0 g. This was dissolved in ether and diluted with a large amount of petroleum ether. After filtration, there was obtained 58.0 g. of solid VIIb, M.P. 99- 101 C. The IR and NMR were consistent with the structure.

Analysis.Calcd. for C H NO F (percent): C, 64.58; H, 6.27; N, 3.96. Found (percent): C, 64.82; H, 6.25; N, 3.82. 7

Example 6 VIII) VIIIb To a cooled (ice-bath) and magnetically stirred solution of 10.5 g. mmole) of VIIb in 80 ml. of dry THF was added dropwise 75 ml. (75 mmole) of 1 M BH /THF solution. After addition, the reaction mixture was kept in a cold room for 18 hours and then at r.t. for 4 hours. It was treated carefully with 3 ml. H 0, 16 ml. 5 N NaOH, 4.4 ml. 30% H 0 and the resulting mixture was heated to an internal temperature of 45-50 C. for 30 minutes. It was then cooled, treated with 100 ml. of cold H 0 and acidified carefully with concentrated HCl. The reaction mixture was extracted with benzene. The benzene solution was dried (Na S0 and evaporated to give 11.7 g. of a crude product, primarily VIIIb.

600 mg. of crude VIIIb was chromatographed through a silica gel column (15 g.). Elution with a mixture of benzene ether (9:1) yielded 100 mg. of an unidentified byproduct (R 0.71 silica, benzenezether, 3:2). Further elution with benzenezether, 1:1) afforded 430 mg. of the desired product (R 0.32 silica, benzenezether, 3:2). The IR and NMR were consistent with the structure.

Analysis.-Calcd. for C H N0 F (percent): C, 61.44; H, 6.51; N, 3.77. Found (percent): C, 61.60; H, 6.74; N, 3.63.

The acidic aqueous solution was basified with NH OH and extracted with CH Cl to give 450 mg. of a basic oil whose structure was not investigated.

Example 7 To a cooled (ice-bath) and stirred mixture of 11.2 g. (30.18 m. mole) of crude VIIIb and 4.51 g. (45 mmole) of solution of 5.16 g. (45 mmole) of mesyl chloride in 10 ml. dry benzene. After addition, the reaction mixture was stirred in the cold for minutes and at r.t. for 3 hours. It was then treated with ml. of water. The layers were separated, and the aqueous layer extracted with CH Cl The combined organic extracts were washed with dilute HCl followed by water. It was dried (Na SO and evaporated to dryness to give a residue which was treated with a small amount of benzene and diluted with a. large amount of ether. The resulting solid was collected by filtration; weight 5.54 g. (41%) of Compound IXb, M.P. 1l6 C. The IR and NMR spectra were consistent with the structure.

Analysis.Calcd. for C H NO SF (percent): C, 53.44; H, 5.83; N, 3.12. Found (percent): C, 52.81; H, 5.72; N, 3.16.

Example 8 To a cooled (ice-bath) and stirred suspension of 0.324 g. (13.5 mmole) of NaH in 5 ml. dry DMF was added dropwise a solution of 4.05 g. (9 mmole) of IXb in 20 ml. dry DM'F. The reaction mixture was stirred at r.t. for 6 hours and then it was cooled, decomposed With 10 ml. of water, and extracted with benzene. The benzene solution was dried (Na SO and evaporated to give 3.55 g. of an oil. This was taken up in ether and extracted with dilute HCl. The ether solution was dried and evaporated to give 1.25 g. of neutral oil Xb. The acidic solution was basified with NH OH, and extracted with CH CI The CH Cl solution was dried and evaporated to give 1.40 g. of basic oil XIIIa.

A sample of neutral oil Xb was distilled B.P. -145 C./ 0.01-0.05 mm. The IR and NMR spectrum of Xb was consistent with the structure.

Analysis.-Calcd. for C H NO F (percent): C, 64.58; H, 6.28; N, 3.96. Found (percent): C, 64.49; H, 6.34; N, 3.97.

The basic oil 1.4 g. was taken up in dry ether, filtered through celite-charcoal, and converted to its -I-IC1 salt in dry ether to give 1.42 g. of HCl salt of XIIIa. A sample was recrystallized from methanol-acetone and dried under 27 high vacuum at 80 C., M.P. 293-295 C. (d). The IR (HCl salt) and NMR (free base) spectra were consistent with the structure.

Analysis.Calcd. for C H NO.HC1 (percent): C, 69.49; H, 8.23; N, 4.77. Found (percent): C, 69.48. H, 8.38; N, 4.62.

By varying the work up temperature, the ratio of products )Cb and XIIIa can be adjusted. In another experiment 9.09 g. (20 mmoles) of Xb in 25 ml. dry THF reacted with 0.72 g. (30 mmole) of NaH in 10 ml. dry DMF under the same condition as above. During the work up, the reaction mixture was well cooled with an ice-bath and then decomposed with ice water. This aiforded 5.7 g. of neutral Compound Xb and 1.1 g. of basic Compound XIIIa.

The basic Compound XIIIa can be obtained from the amide Xb by treatment with NaOH in aqueous ethanol. Thus 5.4 g. of Xb and 20 ml. of 1 N sodium hydroxyde in 80% aqueous ethanol was refluxed for 15 minutes. The reaction mixture was cooled, diluted with water and extracted with ether. After drying and evaporation of the ether, there was obtained 4.0 g. of the basic Compound XIIIa.

A simplified procedure consists in carrying out the above hydrolytic procedure to the mixture of Xb and XIIIa thus leading to a single product, namely the secondary amine XIIIa.

Example 9 H )1 ca K 3 C8 To a cooled (ice-bath) and stirred solution of 5.0 g. (19.45 mmole) of XIIIa and 2.12 g. (21 mmole) of triethylamine in 50 ml. CH CI was added dropwise a solution of 2.49 g. (21 mmole) of cyclobutylcarbonyl chloride in 10 ml. CHZCIQ. After addition, the reaction mixture was treated with water and the layers separated. The CHgClg layer was Washed with dilute HCl and Water. It was dried (Na S0 and evaporated to dryness to give 5.98 g. (90%) of an oil. A sample was distilled B.P. 165- 170 C./0.01-0.05 mm. (Xc) The IR and NMR spectra were consistent with the structure.

Analysis.Calcd. for C H NO (percent): 0, 77.84; H, 8.61; N, 4.13. Found (percent): C, 77.55; H, 8.72; N, 4.01.

Example 10 XIe A solution of 5.67 g. (16.68 g. mole) of Xc in 50 ml. of dry THF was added dropwise to a suspension of 1.0 g. lithium aluminum hydride (LAH) in 10 ml. dry THF at r.t. The reaction mixture was refluxed for 4 /2 hours. There was then added, in succession, 1 ml. H 0, 1 ml. 5 N NaOH and 3 ml. H 0. The reaction mixture was filtered and the cake washed well with ether. The organic filtrate was extracted with dilute HCl and water. The combined acidic solution was basified and extracted with CHgClg. The CHgClg solution was dried and evaporated to give 4.55 g. of basic XIc.

A sample was distilled B.P. 160-165 C./0.01-0.05

mm. The IR and NMR spectra were consistent with the structure.

Analysis.-Calcd for C H NO (percent): C, 81.18; H, 9.60; N, 4.30. Found (percent): C, 81.30; H, 9.67; N, 4.18.

Example 11 XIIc A solution of 4.25 g. (13.05 mmole) of XIc in 130 ml. dry CH Cl was added dropwise during 30 minutes to a cooled (ice-salt bath) and stirred solution of 6.77 g. (27 mmole) of BBr in 10 m1. dry OH Cl After addition, it was stirred at r.t. for 30 minutes. Thereaction mixture was decomposed with water, basified with NH OH and the layers separated. The basic layer was extracted with CH Cl and combined CH Cl solution was dried and evaporated to dryness to give 4.0 g. Xllc. This was converted to its I-ICl salt in acetone with 3 ml. concentrated HCl acid to give 4.0 g. of the salt. The salt was recrystallized twice from ethanol to give 2.1 g. of XIIc, M.P. 263-265 C. (d), as the HCl salt. The IR (HCl salt) and NMR spectra were consistent with the structure.

Analysis.-Calcd for C H NO.HCl (percent): C, 72.49; H, 8.69; N, 4.03. Found (percent): C, 72.27; H, 8.79; N, 4.08.

Example 12 cu o allyl Br v C5 0 XIIIa To a stirred solution of 900 mg. of the amine X1112. and

1.7 g. of triethylamine in absolute methanol (12 m1.) is,

Example 13 Substitution in the procedure of Example 11 for the XIc used therein of XId produces the product XlId.

Example 14 (A) Substitution in the procedure of Example 12 for the allyl bromide used therein of methyl bromide prm duces the product X'Ie.

(B) Substitution in the procedure of Example 11 for the X10 used therein of XIe produces the product Xlle.

CH O

(A) Substitution in the procedure of Example 12 for the allyl bromide used therein of 3,3-dimethylallyl bromide produces the product XIf.

(-B) Substitution in the procedure of Example 11 for the XIc used therein of XIf produces the product XIIf.

Example 16 (A) Substitution in the procedure of Example 10 for the Compound Xc used therein of Compound Xa produces the Compound XIa.

(B) Substitution in the procedure of Example 11 for the Compound XIc used therein of Compound XIa produces the Compound XHa.

Example 17 XIz A mixture of X'Iz (0.1 mole), 160 ml. of n-octanol and 28.0 g. of KOH pellets is refluxed under nitrogen for 45 minutes. After cooling, the mixture is treated with water and ether (600 ml.). The water layer is discarded, and the organic layer is extracted with 300 ml. of 2 N HCl and 2X 300 ml. of water. The combined aqueous extracts are basified with aqueous ammonia and the free base is taken up in ether, to yield the product XIIIa after drying over K C0 and evaporation. The product is characterized by conversion to the oxalate salt in anhydrous ether which is recrystallized from an acetone-methanol mixture.

We claim: 1. A process for the preparation of compounds having the formula (XIIIb) in which R is (lower)alkyl of 1 to carbon atoms, which process comprises the consecutive steps of (A) acylating one mole of the compound having the formula 30 in which R is (lower)alkyl of 1 to 10 carbon atoms,

with at least one mole of an acylating agent having the formula in which X is OH, Cl, Br or I, R is (lower)alkyl of 1 to 10 carbon atoms, --CF (lower)alkoxy of l to 10 carbon atoms, phenyl, phenoxy, benzyl or benzyloxy, in the presence of at least one mole of a tertiary amine selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine to produce the compound having the formula n 0 2 N -R (VIIr) in which R and R are as above, which is isolated; (B) treating one mole of Compound VHr with at least two moles of boron trihydride, in an organic solvent selected from the group consisting of dry tetrahydrofuran, benzene, dioxane, diethyl ether, dipropyl ether and dibutyl ether and subsequently with at least one mole of hydrogen peroxide and water in the presence of an alkali metal hydroxide to produce the compound having the formula (V I) in which R and R are as above, which is isolated; (C) esterifying one mole of Compound VIIIr by treatment with at least one mole of a (lower) alkyl of 1 to 10 carbon atoms, benzene or toluene sulfonyl halide, in the presence of at least one mole of a tertiary amine selected from the group consisting of triethyla-mine, trimethyla-mine, pyridine, N-methylpiperidine and N-methylpyrrolidine to produce the compound having the formula (IXr) in which R and R are as above and R is (lower)- alkyl, phenyl or tolyl, which is isolated;

(D) cyclizing one mole of Compound IXr by treat- [ment with at least one mole of sodium hydride, in an inert solvent selected from the group consisting of dimethylformamide, dimethylacetamide, benzene, toluene, xylene, tetrahydrofuran and dioxane to produce the compound having the formula in which R and R are as above, which is isolated; and

(E) hydrolyzing Compound Xr with an alkali metal hydroxide to produce compound XII'b.

2. A process of claim 1 wherein in step (A) on mole of Compound V is acylated with about 1 to about 1.5 moles of acylating agent, in an organic solvent selected from the group consisting of methylene chloride, benzene, xylene, ether, dichloroethane and chloroform, in the presence of at least one mole of a tertiary amine selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylpiperidine N-methylpyrrolidine to produce Compound VIIr; in step (B) one mole of Compound VIIr is treated with about 1.5 to about 4 moles of boron trihydride, in an anhydrous organic solvent selected from the group consisting of dry tetrahydrofuran, benzene, dioxane, diethyl ether, dipropyl ethyl and dibutyl ether for about two to 24 hours, at a temperature in the range of about C. to about 30 C., following which the mixture is treated with at least an equimolar quantity each of hydrogen peroxide, water and an alkali metal hydroxide with the aid of heat to produce the compound having the Formula VIHr; in step (C) esterifying one mole of Compound VIIIr with about 1.0 to 2.0 moles of a (lower) alkylsulfony chloride, in the presence of about 1.0 to 3.0 moles of a tertiary amine selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylpiperidine and N-methylpyrrolidine, in an organic solvent selected from the group consisting of benzene, xylene, toluene, methylene chloride and dischloroethane, to produce Compound IXr; in step (D) cych'zing one mole of Compound IXr by treatment with about 1.0 to about 2.0 moles of sodium hydride in an organic solvent selected from the group consisting of dimethylformamide, di-methylacetamide, benzene, toluene, xylene, tetrahydrofuran, and dioxane, at about room temperature for a period of about to about 24 hours, to produce Compound Xr; and in step (E) hydrolyzing Compound Xr with at least an equimolar quantity of sodium or potassium hydroxide in a mixture of water and a (lower)alkanol of 1 to carbon atoms with the aid of heat to produce Compound XIIb.

3. The process of claim 1 wherein in step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to about 1.3 moles of acylating agent in methylene chloride or dichloroethane, in the presence of about 1 to about 2 moles of triethylamine or pyridine to produce Compound VIIr; in step (B) treating one mole of Compound VHr with about 2 to about 3 moles of boron trihydride in tetrahydrofuran or dioxane, and 1 to 2 moles each of hydrogen peroxide, water and sodium or potassium hydroxide to produce Compound VIIIr; in

step (C) esterifying one mole of Compound VIIIr with about 1.1 to about 1.6 moles of methyl sulfonyl chloride, in the presence of about 1.1 to about 1.6 moles of triethylamine or pyridine in benzene, toluene or xylene to produce Compound IXr; in step (D) cyclizin g one mole of Compound IXr with about 1.3 to 1.7 moles of sodium hydride in dimethylformamide or dimethylacetamide to produce Compound Xr; and in step (E) hydrolyzing one mole of Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower) alkanol of 1 to 4 carbon atoms with the aid of heat to produce Compound XIIIb in which R is methyl.

4. The process of claim 1 wherein in step (A) one mole of Compound V in which R is methyl is acylated with about 1.0 to 1.3 moles of ethyl chloroformate or tnfluoroacetic acid anhydride in methylene chloride, in the presence of 1.0 to 1.3 moles of triethylamine to produce Compound VIIr; in step (B) treating one mole of Compound VIIr with about 2 to 3 moles of boron trihydride in tetrahydrofuran, followed by 1.0 to 1.3 moles each of 30% hydrogen peroxide, water and sodium hydroxide to produce Compound VIIIr; in step (C) esterifying one mole of Compound VIHr with about 1.1 to 1.3 moles of methylsulfonyl chloride, in the presence of 1.1 to 1.3 moles of triethylamine in anhydrous benzene to produce Compound D(r; in step (D) cyclizing one mole of Compound IXr with about 1.4 to 1.6 moles of sodium hydride in dimethylformamide to produce Compound Xr; and in step (E) hydrolyzing Compound Xr with 1.0 to 3.0 moles of sodium or potassium hydroxide in a mixture of water and a (lower)alkanol at about reflux temperatures to produce Compound XIIIb in which R is methyl.

References Cited UNITED STATES PATENTS 2,766,245 10/1956 Gates 260285 3,285,922 2/1972 Gates 260285 OTHER REFERENCES Gates et a1.: Iour. Am. Chem. 800., vol. 80, pp. 1186- 94 (1958).

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260-2835 Y, 456 A, 465 F, 562 R, 562 A, 570.8 R, 570.8 T C, 611; 424 260 

